Azabicyclo amides and esters as 5-HT3 receptor antagonists

ABSTRACT

Novel azabicyclo amides and esters as antagonists at the 5-HT 3  receptor and useful as anti-emetic agents.

BACKGROUND OF THE INVENTION

This invention relates to novel azabicyclo amides and esters which areantagonists at the serotonin 5-HT₃ receptor and useful as anti-emeticagents in warm blooded animals, particularly the emesis associated withthe anticancer drug cisplatin. The 5-HT₃ receptor antagonists of thepresent invention are also useful in the treatment of schizophrenia,migraine, anxiety, cognitive disorders, Alzheimer's disease, pain andgastrointestinal disorders, such as irritable bowel syndrome.

Compounds recognized for their ability to act as antagonists at theserotonin 5-HT₃ receptor sites are described in U.S. Pat. Nos. 4,593,034and 4,749,718 and U.K. Patent Applications 2,125,398A, 2,166,726A,2,166,727A, 2,166,728A and 2,193,633A.

SUMMARY OF THE INVENTION

The novel amides and esters of the present invention are of formula Iand II: ##STR1## and a pharmaceutically acceptable acid addition salt,wherein Ar is an aromatic group such as phenyl, naphthyl, 3-indolyl,3'-indazolyl, 1-methyl-3-indolyl, 2-methoxyphenyl or2-methoxy-4-amino-5-chlorophenyl; and X is O or NH.

Preferred are the compounds of formula I, where X is NH and Ar is3-indolyl, 3-indazolyl or 2-methoxy-4-amino-5-chlorophenyl.

A second preferred group of compounds are those of formula II wherein Xis O and Ar is 3-indolyl or 1-methyl-3-indolyl.

Also considered part of the present invention are the usefulintermediates of the formula ##STR2## wherein Y is Cl, N₃, OH or NH₂.

The present invention also includes a method for treating emesis in ahuman being by administration of an anti-emetic amount of the compoundsof formulae I and II and a pharmaceutical composition for said methodcomprising an effective amount of compounds of formulae I and II.

As previously indicated, the present invention embraces pharmaceuticallyacceptable salts of the biologically active compounds. Such salts arethose which are non-toxic at the dosages administered. Since compoundsof the invention contain basic groups, acid addition salts are possible.Pharmaceutically acceptable acid addition salts include e.g., thehydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, phosphate,acid phosphate, acetate, lactate, maleate, mesylate, fumarate, citrate,acid citrate, tartrate, bitartrate, succinate, gluconate, glutamate,aspartate and saccharate salts.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of formulae I and II wherein X is NH are prepared byacylation of the requisite amine with the appropriate acid as somereactive derivative. Such derivatives include acid halides, acid azides,acid cyanides, mixed acid anhydrides, active esters or active amides.Particularly preferred are acid halides, such as acid chlorides andactive amides, such as acylimidazoles.

Acid chlorides are prepared by methods known to those skilled in the artand usually consist of reacting the acid with a chlorinating agent suchas phosgene, thionyl chloride, phosphorous trichloride, phosphorusoxychloride, phosphorus pentachloride or. oxalylchloride.

Acyl imidazoles are readily prepared by reacting the appropriate acidwith carbonyldiimidazole. The acyl imidazole can be generated in situand used directly in the reaction, or it can be isolated prior to itsuse in the acylation reaction.

The acylation of the amine reagent is usually carried out in areaction-inert solvent which is miscible with water. Such solventsinclude acetone, dimethylformamide, tetrahydrofuran, dimethylsulfoxideand dioxane.

In practice, equimolar amounts of the amine and acylating agent arecombined in the appropriate solvent. Lesser or greater molar amounts ofeither reagents can be employed without changing the course of thereaction. When an acid chloride is employed as the acylating agent, itis preferred that a corresponding molar amount of acid scavenger beemployed. Such scavengers include pyridine, triethylamine, etc.

Reaction temperature is not critical, and the acylation can readily beconducted at room temperature. At such a preferred reaction temperature,the reaction is substantially complete is about one to twelve hours.

The product is isolated by adding the water-miscible solvent to water ora salt solution thereof followed by extraction of the product with awater immiscible solvent such as methylene chloride or chloroform. Onisolation, the product can be purified by classical methods such asrecrystallization or column chromatography.

The compounds of formulae I and II wherein X is O are prepared byacylation of the appropriate alcohol with a reactive derivative of therequisite acid. Such derivatives are the same as those employed in theacylation of the amines as previously described. The preferredderivative is the acid chloride.

In practice, the acid chloride is added to a solution of an equimolaramount of the appropriate alcohol in a water soluble aprotic,reaction-inert solvent such as tetrahydrofuran. To facilitate thereaction it is preferred,that an alkali metal salt of the alcohol beemployed. This can readily be prepared by treating a solution of thealcohol with sodium hydride or an alkyl lithium such as butyl lithium,prior to the addition of the acid chloride.

Reaction temperature is not critical, and the acylation can readily becarried out at room temperature. At such a preferred reactiontemperature, the reaction is complete in five to seven hours.

The product is obtained and purified by the same procedure as previouslydescribed for the amide products of the present invention.

The starting alcohol leading to the compounds of formula II (X═O) isprepared by the sodium borohydride reduction of the correspondingcommercially available ketone.

Treatment of the resulting alcohol with thionyl chloride leads to anunexpected rearrangement and formation of the compound of formula III(Y═Cl). Treatment of III (Y═Cl) with a tetra alkyl ammonium azide at lowtemperatures leads to the synthesis of III (Y═N₃). Reduction of thisazide with lithium aluminum hydride provides the intermediate III(Y═NH₂).

Treatment of the mesylate of the alcohol required to form compounds offormula II (X═O) with a tetra alkyl ammonium azide gives rise to amixture of two azides as shown: ##STR3##

This mixture, which is comprised mainly of2-methylene-3-azidoquinuclidine (Ca 2:1), can be reduced to a mixture ofthe corresponding amines. This mixture of amines can be used in theacylations previously described and the products subsequently separatedand purified, or the mixture of amines can be converted to therespective t-butoxycarbonyl derivatives and separated. The separatedt-butoxycarbonyl derivative can then be treated with dioxane saturatedwith hydrogen chloride resulting in the deblocking of the amine andisolation of the amine hydrochloride.

As previously mentioned, the compounds of the instant invention areantagonists of 5-hydroxytryptamine (5-HT) at the 5-HT₃ receptors. Thisproperty is demonstrated by their ability to antagonize the effects of5-HT in the Bezold-Jarisch reflex [Richardson, et al., Nature 316, 126(1985)] and their ability to bind to 5-HT receptors in brain tissue[Watling, et al., European J. Pharmacol. 149, 397 (1988)]. The compoundsof the present invention are especially useful in controlling emesis dueto administration of platinum anti-cancer agents. Evaluation of thesecompounds as anti-emetic agents against cisplastin uses the procedure inCylys, Res. Commun. Chem. Pathol. Pharmacol., 23, 61 (1979).

The compounds of the present invention can be administered as antiemeticagents by either the oral or parenteral routes of administration, withthe former being preferred for reasons of patient convenience andcomfort. In general, these antiemetic compounds are normallyadministered orally in dosages ranging from about 5 mg to about 10 mgper kg of body weight per day and 0.1 mg to about 1.0 mg per kg of bodyweight per day when given parenterally; variations will necessarilyoccur depending upon the condition of the subject being treated and theparticular compound being administered. Typically, treatment iscommenced at a low daily dosage and increased by the physician only ifnecessary. It is to be noted that these compounds may be administered incombination with pharmaceutically acceptable carriers by either of theroutes previously indicated, and that such administration can be carriedout in both single and multiple dosages.

The novel compounds of the invention can be orally administered in awide variety of different dosage forms, i.e., they may be formulatedwith various pharmaceutically acceptable inert carriers in the form oftablets, capsules, lozenges, troches, hard candies, powders, sprays,aqueous Suspensions, elixirs, syrups, and the like. Such carriersinclude solid diluents or fillers, sterile aqueous media and variousnon-toxic organic solvents, etc. Moreover, such oral pharmaceuticalformulations can be suitably sweetened and/or flavored by means ofvarious agents of the type commonly employed for such purposes. Ingeneral, the compounds of this invention are present in such oral dosageforms at concentration levels ranging from about 0.5% to about 90% byweight of the total composition, in amounts which are sufficient toprovide the desired unit dosages.

For purposes of oral administration, tablets containing variousexcipients such as sodium citrate, calcium carbonate and calciumphosphate may be employed along with various disintegrants such asstarch and preferably potato or tapioca starch, alginic acid and certaincomplex silicates, together with binding agents such aspolyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often very useful for tabletting purposes. Solid compositionsof a similar type may also be employed as fillers in soft andhard-filled gelatin capsules; preferred materials in this connectionwould also include lactose or milk sugar as well as high molecularweight polyethylene glycols. When aqueous suspensions and/or elixirs aredesired of oral administration, the essential active ingredient thereinmay be combined with various sweetening or flavoring agents, coloringmatter or dyes and, if so desired, emulsifying and/or suspending agentsas well, together with such diluents as water, ethanol, propyleneglycol, glycerin and various like combinations thereof.

The following examples illustrate the invention but are not to beconstrued as limiting the same.

EXAMPLE 1N-(2,3-Dehydroquinuclidin-2-ylmethyl)-2-methoxy-4-amino-5-chlorobenzamide(I: Ar═2--CH₃ O--4--NH₂ --5--Cl--C₆ H₂ ; X═NH)

Under a nitrogen atmosphere, in a round-bottom flask were placed 363 mg(1.8 mmol) of 2-methoxy-4-amino-5-chlorobenzoic acid and two mL oftetrahydrofuran. To the system was added 586 mg (3.6 mmol) of carbonyldiimidazole. The reaction mixture was stirred for 40 minutes,partitioned between chloroform and water and extracted with chloroform.The organic phase was dried (Na₂ SO₄) and concentrated with a rotaryevaporator. To the system was added 250 mg (1.8 mmol) of2-aminomethyl-2,3-dehydroquinuclidine in two mL tetrahydrofuran, and thereaction mixture was stirred at room temperature overnight. The reactionmixture was partitioned between chloroform and saturated aqueous sodiumbicarbonate and extracted with chloroform. The organic phase was dried(Na₂ SO₄) and concentrated, and the crude product was purified by flashcolumn chromatography (25 g of silica gel) using 1:9 methanol/chloroformas the eluant to obtain 133 mg of white solid. This material wastriturated with ether to obtain 85 mg of pure product as a white solid,mp 202°-204° C. ¹ HNMR (CDCl₃) delta1.48 (m, 2H), 1.58 (m, 2H), 2.54 (m,3H), 2.92 (m, 2H), 3.86 (s, 3H), 3.99 (d, 2H, J=6), 6.24 (s, 1H), 6.28(d, 1H, J=6), 7.22 (s, 1H) HRMS: Calcd for C₁₆ H₂₀ N_(3O) ₂ Cl³⁵ :321.1244. Found: 321.1198.

EXAMPLE 2

Starting with the appropriate reagents and using the procedure ofExample 1, the following compounds were prepared: ##STR4## ¹ HNMR(CDCl₃) delta 1.34 (m,2H), 1.52 (m, 2H), 2.50 (m, 3H), 2.90 (m, 2H),3.98 (d, 2H, J=6), 6.29 (d, 1H, J=6), 7.34 (m, 3H), 7.72 (d,2H, J=6).HRMS: Calcd. for C₁₅ H₁₈ N₂ O: 242. 1419. Found: 242.1388. Calcd. forC₁₅ H₁₈ N₂ O×1/2 H₂ O: C, 71.67, H, 7.61, N, 11.14. Found: C, 71.56, H,7.70, N, 11.03. ##STR5## ¹ HNMR (CDCl₃) delta 1.64 (m, 4H), 2.74 (m,3H), 3.12 (m, 2H), 4.08 (d, 2H, J=7), 6.68 (d, 1H, J=6), 7.20 (m, 1H),7.34 (t, 1H, J=6), 7.42 (d, 1H, J=6), 8.42 (d, 1H, J=6). HRMS: Calcd.for C₁₆ H₁₄ N₄ O: 282.1481. Found: 282.1487. ##STR6## ¹ HNMR (CDCl₃)delta 1.38 (m, 2H), 1.54 (m, 2H), 2.54 (m, 3H), 2.82 (m, 2H), 4.06 (d,2H, J=6), 6.36 (d, 1H, J=7), 7.18 (m, 2H), 7.38 (m,1H), 7.66 (d, 1H,J=2), 7.96 (m, 1H). HRMS: Calcd. for C₁₇ H₁₉ N₃ O: 281.1528. Found:281.1552.

EXAMPLE 3 1-Methylindole-3-(2-methylenequinuclidin-3-yl)carboxamide (II:Ar═1-methyl-3-indolyl; and X═NH)

Under a nitrogen atmosphere, in a round-bottom flask were placed 0.36mmol of a mixture of 2-aminomethyl-2,3-dehydroquinuclidine and3-amino-2-methylenequinuclidine (ca 1:2) and 0.5 mL of tetrahydrofuran.Tothe system were added 105 mg (0.54 mmol) of 203-chlorocarbonyl-1-methylindole and 54 mg (0.075 mL, 0.54 mmol) oftriethylamine. The reaction mixture was stirred at room temperature forca. one hour, diluted with chloroform, washed with saturated aqueoussodium bicarbonate, dried (Na₂ SO₄) and concentrated with a rotaryevaporator. The crude material was subjected to flash columnchromatography (10 g of silica gel) to obtain 30 mg of the desiredproduct. This material was dissolved in ethyl acetate and hydrogenchloride was bubbled through the solution. The solution was concentratedwith a rotary evaporator to obtain 22 mg of the correspondinghydrochloride as a tan solid, mp 160°-167° C. ¹ HNMR (DMSO-d₆) delta1.84 (m, 1H), 2.02 (m, 2 H), 2.26 (m, 2H), 3.25 (m, 3H), 3.88 (s, 3H),5.06 (m, 1H), 5.46 (s, 1H), 5.94 (s, 1H), 7.23 (m, 2H),7.54 (d, 1H,J=7), 8.16 (d, 1H, J=7), 8.26 (s, 1H), 8.37 (d, 1H, J=7). HRMS(freebase): Calcd. for C₁₈ H₂₁ N₃ O: 295.1684. Found: 295.1683.

EXAMPLE 4 N-(2-Methylenequinuclidin-3-yl)-2-methoxy-4-amino-5-chlorobenzamide (II: Ar═2--CH₃ O--4--NH₂--5--Cl--C₆ H₂ ; and X═NH)

The titled amide product was prepared in a similar manner and has thefollowing spectral properties: ¹ HNMR (CDCl₃) delta 1.44 (m, 1H), 1.68(m, 3H), 2.18 (m, 1H), 2.98 (m, 4H), 3.84 (s, 3H), 4.68 (d, 1H, J=8),4.95 (d, 1H, J=2), 5.08 (d, 1H, J=2), 6.28 (s, 1H), 7.90 (d, 1H, J=8).HRMS: Calcd. for C₁₆ H₂₀ N₃ O₂ Cl³⁵ : 321.1244. Found: 321.1235.

EXAMPLE 5 2-Methylenequinuclidin-3-yl indole-3-carboxylate (II:Ar═3-indolyl; andX═O)

Under a nitrogen atmosphere, in a round-bottom flask were placed 500 mg(3.1 mmol) of indole-3-carboxylic acid and three mL of tetrahydrofuran.Tothe system was added 0.30 mL (3.4 mmol) of oxalyl chloride over aperiod for five minutes, and the reaction mixture was stirred at roomtemperaturefor 1.5 hours and concentrated with a rotary evaporator. In aseparate flask, under a nitrogen atmosphere, were placed 366 mg (2.63mmol) of the alcohol 2-methylene-3-quinuclidinol and three mL oftetrahydrofuran. To this solution, cooled to 0° C., was added slowly1.04 mL (2.6 mmol)of 2.5M n-butyllithium in hexanes, and the mixture wasstirred for five minutes and concentrated. The residue was dissolved inone mL of tetrahydrofuran and added to the acid chloride prepared above(two one mL rinses). The mixture was stirred at room temperature forfive hours and partitioned between chloroform and saturated aqueoussodium bicarbonate. The layers were separated, and the aqueous phase wasextracted with three portions of chloroform. The combined organicfractions were dried (Na₂ SO₄) and concentrated. The crude material waspurified by flash column chromatography (50 g of silica gel) using 1:19methanol/chloroform as the eluant to obtain 435 mg of white foam whichsolidified, mp 99°-109° C. (dec.) ¹ HNMR (CDCl₃) delta 1.54 (m, 1H),1.76 (m, 2H), 2.04 (m, 1H), 2.34 (m, 1H), 3.10 (m, 5H), 5.17 (s, 1H),5.32 (s, 1H), 5.68 (s, 1H), 7.26 (m, 1H), 7.41 (m, 1H),7.84 (m, 1H),8.14 (s, 1H). HRMS: Calcd. for C₁₇ H₁₈ N₂ O₂ :282.1369. Found: 282.1358.

EXAMPLE 6

Employing the procedure of Example 5 and starting with the requisitereagents, the following compounds were prepared: ##STR7## ¹ HNMR(DMSO-d₆) delta 2.0 (m, 4H), 3.44 (m, 5H), 3.86 (s, 3H), 5.62 (s, 1H),5.76 (m, 1H), 5.88 (m, 1H), 7.05 (t, 1H, J=7), 7.19 (d, 1H, J=7), 7.60(t, 1H, J=7), 7.74 (d, 1H, J=7). HRMS: Calcd. for C₁₆ H₁₅ NO₃ :273.1365. Found: 273.1340. ##STR8## ¹ HNMR (CDCl₃) delta 2.02 i(m, 2H),2.16 (m, 1H), 2.40 (m, 1H), 2.71 (m, 1H), 3.48 (m, 2H), 3.64 (m, 2H),5.70 (m, 1H), 5.86 (m, 1H), 6.i48 (s, 1H), 7.62 (m, 2H), 7.94 (m, 4H),8.58 (s, 1H). HRMS: Calcd. for C₁₉ H₁₉ NO₂ : 293.1416. Found: 293.1431.##STR9## ¹ HNMR (CDCl₃) delta 1.58 (m, 1H), 1.82 (m, 2H), 2.06 (m, 1H),2.42 (m, 1H), 3:12 (m, 4H), 5.22 (s, 1H), 5.37 (s, 1H), 5.85 (s, 1H),7.30(t, 1H, J=8), 7.44 (t, 1H, J=8), 7.78 (d, 1H, J=8) 8.14 (d, 1H,J=8). HRMS:Calcd. for C₁₆ H₁₇ N₃ O₂ : 283.1321. Found: 283.1302.##STR10## ¹ HNMR (CDCl₃) delta 1.48 (s, 1H), 1.70 (m, 2H), 1.94 (m, 1H),2.24 (m, 1H), 3.02 (m, 4H), 3.82 (s, 3H), 5.04 (s, 1H), 5.28 (s, 1H),5.53(s, 1H), 7.23 (s, 1H), 7.76 (s, 1H). ##STR11## ¹ HNMR (DMSO-d₆)delta 2.00 (m, 3H), 2.24 (m, 1H), 3.46 (m, 5H),3.92 (s, 3H), 5.i65 (s,1H), 5.84 (s, 1H), 5.98 (s, 1H), 7.31 (m, 2H), 7.61(d, 1H, J=7), 8.00(d, 1H, J=7), 8.30 (s, 1H). HRMS: Calcd. for C₁₈ H₂₀ N₂ O₂ : 296.1525.Found: 296.1504.

EXAMPLE 7 2,3-Dehydroquinuclidin-2-ylmethyl indole-3-carboxylate (I:Ar═3-indolyl; and X═O)

Under a nitrogen atmosphere, in a round-bottom flask are placed 20 mmolof potassium carbonate and 7 mL of water. To the system is added 10 mmolof the product of preparation B1 in 3 mL of tetrahydrofuran, and themixture is stirred until thin layer chromatography indicates that nostarting chloride remains. The mixture is diluted with water andextracted with several portions of methylene chloride. The combineddichloromethane fractions are dried (Na₂ SO₄) and concentrated with arotary evaporator, and the crude product is subjected to flash columnchromatography to obtain 2-hydroxymethyl-2,3-dehydroquinuclidine (III,Y═OH). The procedure of Example 5 is repeated, replacing2-methylene-3-quinuclidinol with III (Y═OH), to obtain the titlecompound.

PREPARATION A 2-Methylene-2-Quinuclidinol

Under a nitrogen atmosphere, in a round-bottom flask were placed 16.7 g(122 mmol) of commercial 2-methylene-3-quinuclidinome and 250 mL ofmethanol. To this stirring solution Was added 4.75 g (125 mmol) ofsodium borohydride in portions over a period of 10 minutes. The reactionmixture was stirred at room temperature for 20 minutes, 200 mL of ethylacetate was added to the system and the mixture was stirred for 10minutes. To thesystem was added cautiously and slowly saturated aqueoussodium bicarbonate. To the mixture were added additional water and ethylacetate,the layers were separated and the aqueous phase was extractedwith ethyl acetate. The combined organic fractions were dried (Na₂ SO₄)andconcentrated. The crude material was purified by flash columnchromatography (400 g of silica gel) using 1:9 methanol/chloroform asthe eluant to obtain 3.8 g of product, mp 90°-92° C. HNMR (CDCl₃) delta1.32 (m, 1H), 1.46 (m, 1H), 1.62 (m, 1H), 1.86 (m, 2H), 2.68 (m, 1H),2.88 (m, 3H), 4.17 (d, 1H, J=2), 4.96 (d, 1H, J=2), 5.08 (d, 1H, J=2).HRMS: Calcd. for C₈ H₁₃ NO: 139.0998. Found: 139.0998. Calcd. for C₈ H₁₃NO: C, 69.03, H, 9.41, N, 10.06. Found: C, 68.63, H, 9.24, N, 10.09.

PREPARATION B 2-Aminomethyl-2,3-dehydroquinuclidine

1. 2-chloromethyl-2,3-dehydroquinuclidine

Under a nitrogen atmosphere, in a round-bottom flask were placed two g(14 retool) of the product of Preparation A and 5 mL of methylenechloride, and the system was immersed in an ice bath. To the system wasadded 5.25 mL (72 mmol) of thionyl chloride dropwise over a period of 5minutes. The ice bath was allowed to expire, and the reaction mixturewas stirred at room temperature overnight. The reaction mixture wasconcentrated with a rotary evaporator, and 2N aqueous sodium hydroxidewas added to the system. To the system was added water and the mixturewas extracted with two portions of methylene chloride. The combinedorganic fractions were dried and concentrated to afford 1.9 g of thetitled product as a yellow oil. ¹ HNMR (CDCl₃) delta 1.38 (m, 2H), 1.56(m, 2H), 2.56 (m, 3H), 2.94 (m, 2H), 3.96 (s, 2H), 6.48 (d, 1H, J=6).Calcd. for C₈ H₁₂ ClN×1/2H₂ O: C, 57.65, H, 7.86, N, 8.40. Found: C,57.92, H, 7.92, N, 8.17.

2. 2-azidomethyl-2,3-dehydroquinuclidine

Under a nitrogen atmosphere, in a round-bottom flask immersed in anice/acetone bath were placed 3 g (19 mmol) of the product of PreparationB1 30 mL of acetonitrile, 2.65 mL (19 mmol) of triethylamine and 10 g(35 mmol) of tetra-n-butylammonium azide, and the reaction mixture wasstirredfor two hours, the temperature of the cold bath gradually risingto -5° C. The reaction mixture was poured into cold saturated aqueoussodium bicarbonate and extracted with cold ethyl acetate. The ethylacetate solution was washed with three portions of cold aqueous sodiumbicarbonate, dried (Na₂ SO₄) and concentrated to obtain 8 g of crudeproduct. This material was dissolved in cold ether/ethyl acetateandwashed with five portions of cold aqueous sodium bicarbonate, dried(Na₂ SO₄) and concentrated (rotary evaporator, cold water bath) toobtain 1.8 g of the allylic azide product as a yellow oil which was usedimmediately for the next transformation. ¹ HNMR (CDCl₃) delta 1.32 (m,2H), 1.50 (m, 2H), 2.28 (m, 2H), 2.94 (m, 2H), 3.26 (m, 1H), 3.65 (s,2H), 6.37 (d, 1H, J=7). HRMS Calcd. for C₈ H₁₂ N₄ : 164.1061. Found:164.1025.

3. 2-Aminomethyl-2,3-dehydroquinuclidine

Under a nitrogen atmosphere, in a round-bottom flask were placed 22 mL(22 mmol) of 1M lithium aluminum hydride tetrahydrofuran, and the systemwas cooled in a dry ice/acetone bath. To the system was added dropwiseover a period of ca. two minutes a solution of 1.8 g (11 mmmol) of thecompound of Preparation B2 in 7.8 mL of tetrahydrofuran and the coldbath was replaced with an ice/acetone bath. The reaction mixture wasstirred for 30minutes, the cold bath was removed and the mixture wasstirred for an additional period of 30 minutes. The system was immersedin an ice/acetonebath, and 10 mL of 2N aqueous sodium hydroxide wasadded slowly and cautiously to the mixture. The system was removed fromthe cold bath, and the reaction mixture was stirred for 10 minutes.Sodium sulfate was added to the mixture, and after 15 minutes the solidswere removed by suction filtration. The filtrate was concentrated with arotary evaporator to obtain 1.67 g of product as a colorless oil whichwas used in subsequent transformations without further purification. ¹HNMR (CDCl₃) delta 1.34 (m, 2H), 1.50 (m, 2H), 2.48 (m, 3H), 2.90 (m,2H), 3.21 (s, 2H), 6 17 (d, 1H, J=7). Mass spectrum, m/z 138 (parent).

PREPARATION C 3-Amino-2-methylenequinuclidine Hydrochloride

1. 2-methylene-3-quinuclidinol mesylate

Under a nitrogen atmosphere, in a round-bottom flask were placed 8 g (58mmol) of the alcohol of Preparation A and 60 mL of tetrahydrofuran. Tothesystem (cooled in an ice/acetone bath) was added 17.9 mL (128 mmol)of triethylamine followed by 5.13 mL (66 mmol) of methanesulfonylChloride over a period of 15 minutes. The mixture was gradually warmedto room temperature and stirred overnight. The reaction mixture waspartitioned between 2N aqueous sodium hydroxide and chloroform, thelayers were separated and the aqueous phase was extracted withchloroform. The combined chloroform fractions were dried (Na₂ SO₄) andconcentrated (rotary evaporator). The crude material was purified byflashcolumn chromatography (300 g of silica gel) using 1:9methanol/chloroform as the eluant to obtain 5.3 g of the desiredproduct. ¹ HNMR (CDCl₃) delta 1.48 (m, 2H), 1.68 (m, 1H), 1.84 (m, 1H),2.28 (m, 1H),2.76 (m, 1 H), 2.94 (m, 3H), 3.04 (s, 3H), 5.08 (d, 1H,J=5), 5.14 (s, 1H),5.24 (d, 1H, J=5).

2. Mixture of 2-methylene-3-azidoquinuclidine and20azidomethyl-2,3-dehydroquinuclidine

Under a nitrogen atmosphere were placed 5.3 g (24 mmol) of the productof Preparation C1 and 65 mL of acetonitrile. To the system was added13.7 g (48 mmol) of tetra-n-butylammonium azide, and the reactionmixture was stirred at 55° C. for 90 minutes and at room temperatureovernight.The reaction mixture was partitioned between saturated aqueoussodium bicarbonate and chloroform, the layers were separated and theaqueous phase was extracted with chloroform. The combined chloroformfractions were dried (Na₂ SO₄) and concentrated with a rotaryevaporator. The crude material was purified by flash columnchromatography (650 g of silica gel) using 1:9 methanol/chloroform asthe eluant to obtain 5.5 g ofcolorless oil. This material was dissolvedin chloroform and extracted withdilute aqueous hydrochloric acid. Theaqueous extract was adjusted to a pH of ca. 7.5 and extracted with threeportions of chloroform. The combined chloroform extracts were dried (Na₂SO₄) and concentrated to afford 3.46 of a mixture (ca. 2:2) of thetitled azides, respectively.

3. Mixture of 2-methylene-3-aminoquinuclidine and2-aminomethyl-2,3-dehydroquinuclidine

Under a nitrogen atmosphere, in a round-bottom flask were placed 42 mL(42 mmol) of 1M lithium aluminum hydride in tetrahydrofuran. The systemwas cooled to -78° C., and the azide mixture prepared above (3.46 g,21.0 mmol) in 15 mL of tetrahydrofuran was added to the system dropwise.The mixture was stirred for 30 minutes, and the cold bath was replacedwith an ice/acetone bath. The mixture was stirred for 30 minutes at roomtemperature, the cold bath was removed and the mixture was stirred atroomtemperature for one hour. The system was cooled in an ice/acetonebath and 20 mL of 2N aqueous sodium hydroxide was added cautiously andslowly to the system. To the system was added Na₂ SO₄, the mixture wasstirred for one hour, the solids were moved by suction filtration andfiltrate was concentrated with a rotary evaporator to obtain 1.9 g of amixture of the titled amines as a pale yellow oil. This mixture was usedwithout further purification to obtain amides.

4. 2-methylene-3-aminoquinuclidine hydrochloride

Under a nitrogen atmosphere, in a round-bottom flask were placed 50 mg(0.36 mmol) of the mixture of amines from Preparation C2 and 0.5 mL ofdi-tert-butyldicarbonate, and the reaction mixture was stirred at roomtemperature for three days. The mixture was partitioned betweendichloromethane and saturated aqueous sodium bicarbonate, and the layerswere separated. The aqueous phase was extracted with dichloromethane,and the combined organic fractions were dried (Na₂ SO₄) and concentratedwith a rotary evaporator. The crude material was subjected toflashcolumn chromatography (15 g of silica gel) to obtain 46 mg of thet-butoxycarbonyl derivative of 2-methylene-3-aminoquinuclidine ¹HNMR(CDCl₃) delta 1.46 (s, 9H), 1.68 (m, 3H), 2.09 (s, 1H), 2.92 (m,4H), 4.26 (m, 1H), 4.76 (m, 1H), 4.95 (s, 1H), 5.09 (s, 1H). Massspectrum, m/z248 (parent) and 13 mg of the t-butoxycarbonyl derivativeof 2-aminomethyl-2,3-dehydroquinuclidine. ¹ HNMR (CDCl₃) delta 1.44(m,10H), 1.6 (m, 2H), 2.16 (m, 1H), 2.52 (m, 3H), 2.92 (m, 2H), 3.70 (m,2H), 6.28 (d, 1H, J=7). Mass spectrum, m/z 248 (parent).

Under a nitrogen atmosphere, in a round-bottom flask were placed 29 mg(0.12 mmol) of the t-butoxycarbonyl derivative of2-methylene-3-aminoquinuclidine and 0.8 mL of dioxane saturated withhydrogen chloride. The mixture was stirred at room temperature for 90minutes and concentrated with a rotary evaporator to obtain 34 mg of thehydrochloride salt of the product as a white solid. ¹ HNMR (DMSO-d₆)delta 1.92 (m, 3H), 2.10 (m, 1H), 2.44 (m, 1H), 3.24 (m, 1H), 3.46 (m,3H), 4.30 (m, 1H), 5.93 (s, 1H), 6.03 (s, 1H). Mass spectrum, m/z 238(parent).

I claim:
 1. A compound of the formulae ##STR12## and a pharmaceuticallyacceptable acid addition salt thereof wherein Ar is phenol, naphthyl,3-indolyl, 3-indazolyl, 1-methyl-3-indolyl, 2-methoxyphenyl or2-methoxy-4-amino-5-chlorophenyl; and X is O or NH.
 2. A compound ofclaim 1, formula I, wherein X is NH.
 3. The compound of claim 2, whereinAr is 3-indolyl.
 4. The compound of claim 2, wherein Ar is 3-indazolyl.5. The compound of claim 2, wherein Ar is2-methoxy-4-amino-5-chlorophenyl.
 6. A compound of claim 1, formula II,wherein X is O.
 7. The compound of claim 6, wherein Ar is 3-indolyl. 8.The compound of claim 6, wherein Ar is 1-methyl-3-indolyl.
 9. A compoundof the formula ##STR13## wherein Y is Cl, N₃ or NH₂.
 10. A method fortreating emesis in a human being which comprises administering to saidhuman being an anti-emetic effective amount of a compound according toclaim
 1. 11. A pharmaceutical composition comprising an anti-emeticeffective amount of a compound according to claim 1 and apharmaceutically acceptable diluent or carrier.